In vivo and in vitro observations in several different animal models of diabetes and in human erythrocytes indicate that elevated glucose levels per se, independent of the diabetic milieu, induce metabolic imbalances that cause hypoxia-like reductive stress. Several metabolic imbalances induced by the diabetic milieu may contribute to reductive stress, however the best characterized imbalance is increased oxidation of sorbitol to fructose couples to reduction of NAD+ to NADH by sorbitol dehydrogenase. Reductive stress contributes to oxidative stress via several mechanisms and impacts on the activity of numerous enzymes and biochemical imbalances implicated in the pathogenesis of diabetic complications. Metabolically-induced reductive stress appears to be a characteristic feature of poorly controlled diabetes which precedes, and contributes to, development of diabetic complications in general including ischemic retinopathy and neuropathy.